Review on: THE PHARMACEUTICAL PACKAGING

7.1-function of a closure:
• Provide a totally humetic seal.
• Provide an effective seal which is acceptable to the products.
• Provide an effective microbiological seal.

7.2-characteristics of closure:
• It should be resistant and compatible with the product and the product /air space
• If closure is of re closable type, it should be readily operable and should be re-sealed effectively.
• It should be capable of high speed application where necessary for automatic production without loss of seal efficiency.
• It should be decorative and of a shape that blends in with the main containers.

7.3.1-Threaded Screw Cap:The screw cap when applied overcome the sealing surface irregularities and provides physical and chemical protection to content being sealed. The screw cap is commonly made of metal or plastics. The metal is usually tinplate or aluminum, and in plastics, both thermoplastic and thermosetting materials are used. Metal caps are usually coated on the inside with an enamel or lacquer for resistance against corrosion. Almost all metal crowns and closures are made from electrolytic tinplate, a tin-coated steel on which the tin is applied by electrolytic deposition.

PHOTO 7.1:THREADED SCREW CAP

7.3.2-Lug Cap:The lug cap is similar to the threaded screw cap and operates on the same principle. It is simply an interrupted thread on the glass finish, instead of a continuous thread. It is used to engage a lug on the cap sidewall and draw the cap down to the sealing surface of the container. Unlike the threaded closure, it requires only a quarter turn.The lug cap is used for both normal atmospheric-pressure and vacuum-pressure closing. The cap is widely used in the food industry because it offers a hermetic seal and handles well in sterilization equipment and on production lines.

7.3.3-Crown Caps:
This style of cap is commonly used as a crimped closure for beverage bottles and has remained essentially unchanged for more than 50 years.

7.3.4-Roll-On Closures:The aluminum roll-on cap can be sealed securely, opened easily, and resealed effectively. It finds wide application in the packaging of food, beverages, chemicals, and pharmaceuticals. The roll-on closure requires a material that is easy to form, such as aluminum or other light-gauge metal. Re sealable, non re sealable, and pilfer proof types of the roll-on closure are available for use on glass or plastic bottles and jars. The manufacturer purchases these closures as a straight-sided thread less shell and forms the threads on the packaging line as an integral part of the filling operation. The roll-on technique allows for dimensional variation in the glass containers; each roll-on closure precisely fits a specific container.15

PHOTO 7.2: ROLL-ON CLOSURES7.3.5-Pilfer proof Closures:
The pilfer proof closure is similar to the standard roll-on closure except that it has a greater skirt length. This additional length extends below the threaded portion to form a bank, which is fastened to the basic cap by a series of narrow metal "bridges." When the pilfer proof closure is removed, the bridges break, and the bank remains in place on the neck of the container. The closure can be re sealed easily and the detached band indicates that the package has been opened. The torque is necessary to remove the cap.

7.4-Closure lines:
A liner may be defined as any material that is inserted in a cap to effect a seal between the closure and the container.Liners are usually made of a resilient backing and a facing material. The backing material must be soft enough to take up any irregularities in the sealing surface and elastic enough to recover some of its original shape when removed and replaced.

8)Factors in Selecting a Liner:
Many factors have to be considered before an effective liner can be selected. The most important consideration is that the liner be chemically inert with its product, so that the latter is protected against any possible change in purity or potency.Gas and vapor transmission rates are usually relative and depend chiefly on the shelf life required for the product. If the period between packing and consumer use is expected to be long, low transmission rates are necessary16.

8.1-Composition of closure:
Closures are made of
• Rubber
• Plastics

8.1.1-Plastic closures:
The two basic types of plastic generally used for closures are thermosetting and thermoplastic resins. They differ greatly in physical and chemical properties. And fundamentally different manufacturing methods are used for each type:
Thermosetting resins:
Phenolic and urea thermosetting plastic resins are widely used in threaded closures. The thermosetting plastic first softens under heat and then curves and hardens to a final state. Shaping must occur in the first stage of softening, because after curving there is no further mobility, even upon reapplication of heat and pressure. During the molding process, thermosets undergo a permanent chemical change, and unlike thermoplastic material, they cannot be reprocessed. Since parts that are improperly molded must therefore be discarded, thermosetting materials are usually fabricated by compression molding. The manufacturing process is relatively slow, but allows better control and quick response to change in temperature and material is slow.
Phenolics:
Phenolic molding compounds are available in different grades and in dark colors, usually black or brown. Phenolic compounds are used when a hard sturdy piece is needed and when dark colors are well tolerated. Rigidity, heat, chemical resistance strengths are the outstanding properties of the phenolic compounds. Color limitation is the main drawback, although coatings are available at a premium price as a closure, the phenolic can withstand the torquing forces of the capping machines and maintains tight seal over a long period of time.The phenolic compounds are resistant to some dilute acids and alkalies. Organic acids and reducing acids usually do not have any effect. Strong alkaies decompose phenolic

Urea:
Urea is a hard translucent material. Urea is more expensive than the phenolic compounds, but the heat resistance and other properties of urea make it suitable for premium items. Elegant colours are obtained with urea because the translucency give brightness and color depth. Urea plastic is available in unlimited range of colours and is a hard, brittle material that is odorless and tasteless. Being a thermosetting plastic, urea can with stand high temperature without softening, but it chars at about 3900F. Urea absorbs water under wet conditions, but such absorption has no serious effect on the plastic.Urea is not affectd by any organic solvents, but it is affected by alkaies and strong acids. Urea cannot be steam sterilized but can withstand elevated temperature. Parts may shrink as much as 0.003inch after molding.

Thermoplastics resins:
Since their introduction, thermoplastic have become widely used in the manufacture of closures. Polystyrene, polyethylene and polypropylene are the materials used in 90% or more of all thermoplastic closures. Each material has specific performance advantage. The particular resins used depends on the physical and chemical properties desired for the particular products being packaged.

8.1.2-Rubber closures:
Rubber is used in the pharmaceutical industry to make closures, cap liners and bulbs for dropper assemblies. The rubber stopper is used primarily for multiple dose vials and disposable syringes. The rubber polymers most commonly used are natural, neoprene and butyl rubber. Butyl rubber, nitrile rubber are some synthetic rubbers used for the manufacturing of closures.
In the manufacture of rubber closures the types of ingredients commonly found are:
• Rubber
• Vulcanizing agents
• Accelerator/ activator
• Extended filer
• Reinforced filler
• Softener / plasticizer
• Antioxidant
• Pigment
• Special components waxes.
Since the composition of rubber stopper is complex and the manufacturing process is complicated it is common to encounter problems with certain rubber formulas. For example, when the rubber stopper comes in contact with parenteral solution, it may absorb active ingredient, antibacterial preservative or other materials and one or more ingredients of the rubber may be extracted in to the liquid. These extractives could
• Interface with chemical analysis of the active ingredient
• Affect the toxicity or pyrogenicity of the injectable product.
• Interact with the drug preservative to cause inactivation.
• Affect the chemical and physical sterility of the preparation so that particulate matter appears in the solution.

B.P requirmets for rubber closures:
Rubber closures for containers used for aqueous parenteral preparations, powders and freeze dried products are made of materials obtained by vulcanization(cross-linking) of macromolecular organic substance (elastomers) with appropriate additives.

8.2-Tests to control quality of rubber caps:
This include tests for
1) Quality:
The closures should not be tachy after:
• Washing with detergent and rinsing several times.
• Autoclaving at 1210C for half an hour in distilled water.
1) Drying at 650c in vacuum for a day.
2) Finish:
Closures must be substantially free from dust, fibers, loose particles of rubber, smears of grease and pigment and quite free from internal foreign matter.
3) Penetrability:
The closure is sealed into a vial and the force required to make a hypodermic needle penetrate is measured using the piercing machine. The vial is moved on to the needle at a specified speed. The force must not exceed a stated value.
4) Fragmentation:
Test is carried out by using piecing machine with the vial.The vials are half filled with particle free water . Each closure is penetrated with a hypodermic needle (0.08mm external diameter) within a limited area and the last time the needle is washed to transfer fragments from bore to vial .Then the contents are filtered through paper (pore size 0.5mm) of a color that contrasts with the rubber and the fragments are counted by eye. The test is carried out on 20 closures using a fresh needle for each if the previous one has become blunt. These must not be more than average of 3 fragments per closure.17
5)Self sealability:
Two tests are applied:
• In the first, closed vials, half filled with water are inverted and air, equal to the volume inside, is injected. Then the needle of water from the hole or more than a droplet on the surface.
• In the second, methylene blue solution is used instead of water and 25 needle punctures are made evenly within a circle of 5mm diameter to which a prescribed vacuum is applied (or reduced pressure of 27Kpa for 10 minutes, kept for 30 minutes in atmospheric pressure) for half an hour . There must be no signs of leakage in the water or on the closure.
6) Water extractive Test:
Extraction with boiling water is made under reflux for four hours and evaporated to dryness. Weight of the residue must be not more than 2mg for type I and not more than 4mg for type II rubber.
7) Acid or Alkali Treatment:
Specified number of closures are autoclaved with a given volume of freshly boiled and cooled distilled water of PH 6.8 – 7.2. The acid or alkali needed for the neutralization of this extract should be within the limit, i.e. not more than 0.3ml of 0.01M sodium hydroxide or 0.8ml of 0.01 hydrochloric acid.
8) Compatibility with contents:
• Sterile products are packed aseptically in sterile containers and are stored at 40, 250, 380 and 500C with prescribed humidity.
• A control is done using a satisfactory rubber closure or ampoule
9) Permeability to water vapor:
The increase in weight of vials containing dry fused calcium chloride is found after storage under the high humidity conditions and compared with the result for containers sealed with closures known to be satisfactory. Weightings are made fortnightly for 3 months.
10) Absorbance:
Rubber cap with 200ml water is autoclaved. Filtered the autoclaved solution through 0.45mm pore sized paper. Measure absorbance at 20-360 nm. Absorbances should not exceed 0.2 for type I & 4 for type II.
11) Test to determine liberation of toxic substances form rubber:
The test involves the preparation of a blood plate, which is then flooded with a heavy inoculum of Streptococcus pyogenes. Previously sterilized rubber samples are placed on the surface and incubated at 370C for 18 to 24 hours. The red blood cells are haemolysed if organisms are growing and therefore there will be rings of un haemolysed blood around the samples if inhibitory substance are liberated.
12) Limit test: When treated with ammonium and heavy metals the limit must be nmt 2ppm.
13) Titration:Rubber in presence of 200 ml water for injection is autoclaved at 1210C for half an hour to 20 ml of 0.002M potassium permanganate. Boil and cool (3mins). Add 1g of potassium iodide & titrate with 0.01 M Na2S2O3 using 0.25 ml of starch solution as indicator. 18